This invention was made with the assistance of grants from the National Institute on Alcohol Abuse and Alcoholism (Grant No. AA 03577) and the National Institute of General Medical Sciences (Grant No. T32 GM 07775). The Government has certain rights in the invention.
The use of aldehyde dehydrogenase (ALDH) inhibitors is one pharmacotherapeutic approach which has been employed for the treatment of alcohol (ethanol) abuse and alcoholism. Examples of these types of compounds presently used clinically are disulfiram (tetraethylthiuram disulfide) (Antabuse.RTM.), and carbimide (citrated calcium carbimide, cyanamide (Temposil.RTM.)). Disulfiram is used throughout the world, whereas calcium carbimide has not been approved by the FDA for use in the United States.
The rationale for the use of ALDH inhibitors such as disulfiram for the treatment of alcoholism, is that they block the metabolism of ethanol. Thus, after ethanol ingestion, inhibitors of liver mitochondrial low Km ALDH cause an increase in the formation of acetaldehyde. Clinically, this leads to tachycardia, hypotension, nausea, and other adverse symptoms that are referred to as the disulfiram-ethanol reaction (DER). Although disulfiram is widely used in the treatment of alcoholism, its use is not without controversy. A number of reports have questioned disulfiram's toxicity and its ability to produce a DER that is effective to deter ethanol ingestion.
Although studies have been carried out for over 40 years in an attempt to delineate the mechanism by which disulfiram inhibits ALDH, this mechanism is not completely understood. Most of the studies investigating this inhibition have been carried out in vitro, and it has been implied from those studies that disulfiram-induced inhibition in vivo occurs by a similar mechanism. It has been only recently that an appreciation of disulfiram's metabolism has evolved, allowing for a better understanding of the relationship between disulfiram bioactivation, liver ALDH inhibition, and the DER. Much of the basic data providing this understanding has been generated in the laboratory of Morris D. Faiman. For example, see J. J. Yourick and M. D. Faiman, Alcohol, 4, 463 (1987); Biochem. Pharmacol., 38, 413, (1989); and B. W. Hart et al., Alcohol, 7, 165 (1990).
As shown in FIG. 1, disulfiram is reduced to diethyldithiocarbamate (DDTC), which is subsequently degraded nonenzymatically to carbon disulfide and diethylamine. DDTC also is methylated to form the ester, diethyldithiocarbamate-methyl ester (DDTC-Me), which then forms S-methyl-N,N-diethylthiolcarbamate (DETC-Me).
B. W. Hart et al., in Alcohol, 7, 165 (1990) synthesized DETC-Me and determined that it is a more potent inhibitor of liver mitochondrial low Km ALDH than either DDTC-Me, DDTC or disulfiram. The dose at which 50% ALDH inhibition (ID.sub.50) occurred after the intraperitoneal (IP) administration of DETC-Me, DDTC-Me or disulfiram was 6.5, 15.5 and 56.2 mg/kg, respectively. The DER produced by DETC-Me in animals is consistent with that seen with disulfiram, DDTC and DDTC-Me. However, Hart et al. also reported that DETC-Me is not an effective in vitro inhibitor of liver mitochondrial low Km ALDH, and concluded that DETC-Me is not the ultimate species responsible for ALDH inhibition.
Therefore, a need exists for simple compounds which are effective to deter alcohol ingestion by inducing the DER at low, non-toxic dosages.